Mixing bag with integral sparger and sensor receiver

ABSTRACT

A mixing bag for use in bioprocessing in which a fluid is received and agitated using an internal fluid-agitating element driven by an external motive device is disclosed. The bag may include an integral sparger and sensor receiver. Related methods are also disclosed.

This application is a continuation of U.S. patent application Ser. No.13/599,652, now U.S. Pat. No. 8,708,319, which is a continuation of U.S.patent application Ser. No. 13/405,609, now U.S. Pat. No. 8,550,439,which is a continuation of U.S. patent application Ser. No. 12/761,111,now U.S. Pat. No. 8,123,199, which is a continuation of U.S. patentapplication Ser. No. 12/341,478, now U.S. Pat. No. 7,992,846, which is adivisional of U.S. patent application Ser. No. 11/304,417, now U.S. Pat.No. 7,469,884, which is a continuation of international application Ser.No. PCT/US05/00464, which claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/535,031, filed Jan. 7, 2004, and U.S.Provisional Patent Application Ser. No. 60/599,960, filed Aug. 9, 2004,the disclosures of which are all incorporated herein by reference.

TECHNICAL FIELD

The present invention relates generally to vessels in which fluids areagitated and, more particularly, to a mixing bag.

BACKGROUND OF THE INVENTION

Most pharmaceutical solutions and suspensions manufactured on anindustrial scale require highly controlled, thorough mixing to achieve asatisfactory yield and ensure a uniform distribution of ingredients inthe final product. Agitator tanks are frequently used to complete themixing process, but a better degree of mixing is normally achieved byusing a mechanical stirrer or impeller (e.g., a set of mixing bladesattached to a metal rod). Typically, the mechanical stirrer or impelleris simply lowered into the fluid through an opening in the top of thevessel and rotated by an external motor to create the desired mixingaction.

One significant limitation or shortcoming of such an arrangement is thedanger of contamination or leakage during mixing. The rod carrying themixing blades or impeller is typically introduced into the vesselthrough a dynamic seal or bearing. This opening provides an opportunityfor bacteria or other contaminants to enter, which of course can lead tothe degradation of the product. A corresponding danger of environmentalcontamination exists in applications involving hazardous or toxicfluids, or suspensions of pathogenic organisms, since dynamic seals orbearings are prone to leakage. Cleanup and sterilization are also madedifficult by the dynamic bearings or seals, since these structurestypically include folds and crevices that are difficult to reach. Sincethese problems are faced by all manufacturers of sterile solutions,pharmaceuticals, or the like, the U.S. Food and Drug Administration(FDA) has consequently promulgated strict processing requirements forsuch fluids, and especially those slated for intravenous use.

In an effort to overcome these problems, the recent trend in thebiotechnology industry is to use disposable plastic bags for a number ofbioprocessing steps. Pre-sterilized disposable plastic bags eliminatethe need for cleaning, sterilization and validation of the containersafter each bioprocessing batch. Their use thus results in substantialsaving in the cost of manufacturing of biopharmaceuticals.

Typically, one of the bioprocessing steps used in such manufacturing isgrowing cell culture(s) in the container, sometimes called a“bioreactor.” A traditional bioreactor is a sterile vessel made out ofstainless steel or glass with highly controlled environmental parametersincluding temperature, pH, oxygen concentration, CO2 concentration,which are monitored by permanent sensors built into the rigid vessel.During the cell growth process, the fluid in the bioreactor must also beagitated in order to maintain uniform distribution of temperature, gasesand nutrients. As noted above, agitation is typically provided by animpeller with the blades housed on the shaft connected to an externalmotor and introduced inside the bioreactor through the dynamic seal inan effort to maintain sterility.

For normal cell growth certain concentration of dissolved oxygen must bemaintained. Also, controlled introduction of other gases like carbondioxide and nitrogen are normally necessary during bioreactor runs. Themost efficient way of introducing gases in to bioreactor fluid issparging, which involves forming small bubbles in the fluid. Suchbubbles have large surface to volume ratio and thus can be dissolvedmore quickly than large size bubbles.

Traditionally, porous solid materials (like titanium) associated withthe rigid bioreactor provide sparging. Alternatively, metal spargingrings with small pre-drilled holes are permanently affixed in some rigidbioreactors. In both cases, the bioreactors are not readily disposableand thus must be cleaned and sterilized before reuse for bioprocessing.

In traditional rigid vessel bioreactor, the impeller, sparger, gas,temperature and pH sensors are reusable components that must be cleanedand sterilized after each batch. In the case of disposable bagbioreactors, it is desirable that all the fluid touching components areonly used once. This presents the challenging task of providinginexpensive fluid-touching components that can be discarded along withthe bag after use.

Another challenge is positioning the components of the bioreactor on theflexible bag. Unlike a rigid vessel, a bioreactor plastic bag (which isbasically thin film) has no shape or structural rigidity. Traditionally,bioreactor components like impeller shafts, spargers, sensors are housedon the rigid walls of the vessel by means of threads, bolts or clamps.Obviously, this method of component attachment does not work for plasticbags.

Thus, a need is identified for an improved manner of providing a mixingbag or flexible vessel with an integrated sparger and sensor(s). Theimprovement provided by the invention would be easy to implement usingexisting manufacturing techniques and without significant additionalexpense. Overall, a substantial gain in efficiency and ease of use wouldbe realized as a result of the improvement, and would greatly expand thepotential applications for which advanced mixing systems may be used,including bioprocessing.

SUMMARY OF THE INVENTION

An apparatus for receiving a fluid and sensing a characteristic thereofusing a sensor element for the fluid, comprising a vessel having aflexible sidewall at least partially defining an interior compartment, aportion of the vessel formed by the flexible sidewall having nopredetermined shape and capable of assuming a particular shape based onthe presence of the fluid in the interior compartment, and a receiverconnected to the vessel for receiving the sensor element.

In one embodiment, a tube is provided for supporting the sensor element,the tube being adapted for positioning in the receiver. The tube ispositioned in contact with the fluid, and is adapted for positioning inthe receiver in contact with the fluid when present. A fluid-imperviousseal also connects the receiver to the vessel. The receiver includes aportion adapted for connecting with a tube, such as a barb arranged on atubular portion of the receiver. The receiver also includes a tubularportion external to the vessel, which may include a passage forreceiving the sensor element.

Another aspect of the disclosure relates to an apparatus comprising aflexible vessel having an interior space bounded by a surface, theflexible vessel being selectively movable between an extended positionwherein a first portion and an opposing second portion are spaced apartand a collapsed position wherein the first portion and the opposingsecond portion are moved closer together relative to the extendedposition, and a connector secured to the second end of the flexiblevessel, the connector having an opening extending therethrough thatcommunicates with the space of the flexible vessel, and an elongatedprobe having a first end and an opposing second end, the second end ofthe probe being positioned within the interior space of the flexiblevessel, the second end of the probe being configured to pass through theopening of the connector, and a sealing layer for sealing opening of theconnector.

In one embodiment, the vessel comprises a bag, and the sealing layercomprises a flexible plastic material. The probe carries a sensorelement for contacting the fluid. The connector is connected to theflexible vessel, and there may be an adhesive for securing the sealinglayer to the connector. The second end of the probe is positioned withinthe interior space, and the space may be sealed by the probe.

Another aspect of this disclosure relates to an apparatus comprising aflexible vessel including a passage, said vessel having an interiorsurface extending between a first end and an opposing second end, theflexible vessel being selectively movable between an extended positionwherein the first end and the opposing second end are spaced apart and acollapsed position wherein the first end and the opposing second end aremoved closer together relative to the extended position; a connectorsecured to the second end of the flexible vessel, the connector havingan opening extending therethrough that communicates with the interiorcompartment of the flexible vessel, and an elongated tube having a firstend and an opposing second end, the second end of the tube beingpositioned within the interior compartment of the flexible vessel, thesecond end of the tube being configured to pass through the opening ofthe connector, said tube carrying at least one sensor element.

The apparatus may include a flexible plastic material for forming a sealbetween the tube and the connector. The vessel may comprise a bag.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1, 1 a, 1 b and 1 c are partially schematic, partiallycross-sectional side views of one embodiment of a vessel in the form ofa bag having a flexible portion and a rigid portion;

FIG. 2 is a partially schematic, partially cross-sectional side viewshowing the vessel of FIG. 1 positioned in a rigid vessel, with thefluid-agitating element aligned with and levitated/rotated by anadjacent motive device;

FIG. 3a is partially schematic, partially cross-sectional side viewshowing another embodiment of the vessel, including a hat or cap-shapedrigid portion having a cavity facing inwardly;

FIG. 3b is a side view similar to FIG. 3 a;

FIG. 4a is partially schematic, partially cross-sectional side viewshowing another embodiment of the vessel, including a hat or cap-shapedrigid portion having a cavity facing outwardly;

FIG. 4b is a side view similar to FIG. 4 a;

FIGS. 5a, 5b, 6a, 6b, and 7a, 7b are each partially schematic, partiallycross-sectional side views of a vessel with a rigid portion for aligninga fluid-agitating element with a external structure, wherein thefluid-agitating element is directly supported by a slide bearing;

FIG. 8 schematically illustrates one possible embodiment of an integralsparger;

FIG. 9 schematically illustrates another possible embodiment of anintegral sparger;

FIGS. 10a and 10b show yet another possible embodiment of an integralsparger; and

FIG. 11 illustrates an embodiment of a bag including a sensor receiver.

DETAILED DESCRIPTION OF THE INVENTION

Reference is now made to FIG. 1, which discloses one embodiment of thevessel of the present invention in the form of a bag 10. In thisembodiment, the bag 10 includes a body having a flexible or non-rigidportion 12, which is illustrated schematically, and a rigid or stiffportion 14, which is shown in cross-section. However, as outlinedfurther in the description that follows, the use of the many of thepresent inventive concepts disclosed herein with vessels that arecompletely rigid is also possible.

The bag 10 may be hermetically sealed and may have one or more openingsor fittings (not shown) for introducing or recovering a fluid.Alternatively, the bag 10 may be unsealed or open-ended. The particulargeometry of the bag 10 employed normally depends on the application andis not considered critical to the invention. For example, in the case ofa sterile fluid, a hermetically sealed, pre-sterilized bag with anaseptic fitting might be desirable; whereas, in the case where sterilityis not important, an open-ended or unsealed bag might be suitable. Themain important point is that the bag 10 is capable of receiving and atleast temporarily holding a fluid (which is used herein to denote anysubstance capable of flowing, as may include liquids, liquidsuspensions, gases, gaseous suspensions, or the like, withoutlimitation).

The rigid portion 14 includes a first receiver 16 for receiving andholding a fluid-agitating element 18 at a home location (or expectedposition), when positioned in the bag 10. It is noted that “holding” asused herein defines both the case where the fluid-agitating element 18is directly held and supported by the first receiver 16 (see below)against any significant side-to-side movement (save tolerances), as wellas where the first receiver 16 merely limits the fluid-agitating elementto a certain degree of side-to-side movement within the bag 10. In thisembodiment, an opening 18 a is provided in the fluid-agitating element18 and the first receiver 16 is a post 20 projecting toward the interiorof the bag 10 (see FIGS. 1a and 1b ). The post 20 is sized for receivingthe fluid-agitating element 18 by extending through the opening 18 aformed in the body 18 b thereof (which is depicted as being annular, butnot necessarily circular in cross-section). As illustrated in FIG. 1, itis preferable that the size of the opening 18 a is such that thefluid-agitating element 18 may freely rotate and move in the axialdirection along the post 20 without contacting the outer surfacethereof. Despite this freedom of movement, the post 20 serving as thefirst receiver 16 is still considered to hold, confine, or keep thefluid-agitating element 18 at a home location or expected positionwithin the vessel 10 by contacting the surface adjacent to the opening18 a as a result of any side-to-side movement (the boundaries of whichare defined by the dimensions of the opening).

The flexible portion 12 of the bag 10 may be made from one or moresheets of thin (e.g., having a thickness of between 0.1 and 0.2millimeters) polyethylene film secured together to define a compartmentfor receiving the fluid. Preferably, the film used is clear ortranslucent, although the use of opaque or colored films is alsopossible. The rigid portion 14 including the post 20 may be formed ofmaterials, such as high density polyethylene (HDPE), ultrahigh molecularweight (UHMW) polyethylene, or like materials. Of course, thesematerials do have some inherent flexibility when used to form relativelythin components or when a moderate amount of bending force is appliedthereto. Despite this flexibility, the rigid portion 14 is distinguishedfrom the flexible portion 12, in that it generally maintains its shapeunder the weight of fluid introduced in the bag 10.

Optionally, the post 20 may include a portion 20 a for capturing thefluid-agitating element 18 and assisting in holding it thereon. Theportion 20 a is preferably oversized and forms the head or end of thepost 20. By “oversized,” it is meant that at least one dimension(length, width, diameter) of this portion 20 a of the post 20 is greaterthan the corresponding dimension of the opening 18 a in thefluid-agitating element 18. For example, the portion 20 a is shown inFIG. 1 as being disc-shaped, such that it provides the head end of thepost 20 with a generally T-shaped cross section. To prevent interferencewith the levitation and rotation of the fluid-agitating element 18, theoversized portion 20 a is strategically positioned at a certain distancealong the post 20. In the case where it is oversized, the post 20 may beremovably attached to the rigid portion 14 through the opening 18 a inthe fluid-agitating element 18 (such as by providing a threaded bore inthe rigid portion for receiving a threaded end of the post, or as shownin FIG. 1c , a bore 14 a having a groove 14 b for establishing asnap-fit engagement with a corresponding projection 20 b on a taperedend portion 20 c of the post). In the case where the post 20 isunitarily formed with the rigid portion 14 and includes an oversizedhead portion 20 a, this portion should be sufficiently thin such that itflexes or temporarily deforms to allow the fluid-agitating element 18 topass initially (see FIG. 1b and note action arrow A, which demonstratesthe direction of force for deforming the oversized head 20 a such thatit passes through the opening 18 a).

Alternatively, this portion 20 a of the post 20 need not be oversized,as defined above, but instead may simply be sufficiently close in sizeto that of the opening 18 a such that the fluid-agitating element 18must be precisely aligned and register with the post 20 in order to bereceived or removed. In any case, it is again important to note that thefluid-agitating element 18 is held in place in the vicinity of the post20, but remains free of direct attachment. In other words, while thefirst receiver 16 (post 20) confines or holds the fluid-agitatingelement 18 at a home location or expected position within the bag 10, itis still free to move side-to-side to some degree (which in this case isdefined by the size of the opening 18 a), and to move along the firstreceiver 16 in the axial direction (vertical, in the embodiment shown inFIG. 1), as is necessary for levitation.

As perhaps best shown in FIG. 1a , the rigid portion 14 in thisembodiment further includes a substantially planar peripheral flange 22.The flange 22 may be any shape or size, and is preferably attached orconnected directly to the bag 10 at the interface I between the twostructures (which may be created by overlapping the material forming theflexible portion 12 of the bag on an inside or outside surface of theflange 22 to form an overlapping joint, or possibly in some cases byforming a butt joint). In the case where the bag 10 and flange 22 arefabricated of compatible plastic materials, the connection may be madeusing well-known techniques, such as ultrasonic or thermal welding (heator laser) at the interface to form a seal (which is at leastliquid-impervious and preferably hermetic). Alternatively, other meansof connection (e.g., adhesives), may be used at the interface I,although this is obviously less preferred in view of the desirability inmost cases for the more reliable, leak-proof seal afforded using weldingtechniques. In either case, the judicious use of inert sealants may bemade along the joint thus formed to ensure that a leak-proof, hermeticseal results. As discussed further below, the need for such an interfacemay be altogether eliminated by simply affixing the rigid portion 14 toan inside or outside surface of the bag 10.

As should be appreciated, the bag 10 shown in FIG. 1 may be manufacturedas described above, with the fluid-agitating element 18 received on thepost 20 (which may be accomplished using the techniques shown in FIGS.1b and 1c ). The empty bag 10 may then be sealed and folded forshipping, with the fluid-agitating element 18 held at the home locationby the post 20. Holding in the axial direction (i.e., the verticaldirection in FIG. 1) may be accomplished by folding the bag 10 over thepost 20, or by providing the portion 20 a that is oversized or veryclose in size to the opening 18 a in the fluid-agitating element 18.

When ready for use, the bag 10 is then unfolded. It may then be placedin a rigid or semi-rigid support structure, such as a container C,partially open along at least one end such that at least the rigidportion 14 remains exposed (see FIG. 2). Fluid F may then be introducedinto the bag 10, such as through an opening or fitting (which may be asterile or aseptic fitting, in the case where the bag 10 ispre-sterilized or otherwise used in a sterile environment). As should beappreciated, in view of the flexible or non-rigid nature of the bag 10,it will generally occupy any adjacent space provided in an adjacentsupport structure or container C when a fluid F (liquid or gas underpressure) is introduced therein (see FIG. 2).

An external motive device 24 is then used to cause the fluid-agitatingelement 18 (which is at least partially magnetic or ferromagnetic) to atleast rotate to agitate any fluid F in the bag 10. In the embodiment ofFIG. 2, the fluid-agitating element 18 is at least partially magneticand is shown as being levitated by the motive device 24, which isoptional but desirable. As described in my U.S. Pat. No. 6,758,593, thedisclosure of which is incorporated herein by reference, the levitationmay be provided by a field-cooled, thermally isolated superconductingelement SE (shown in phantom in FIG. 2) positioned within the motivedevice 24 and thermally linked to a cooling source (not shown). As alsodescribed therein, the fluid-agitating element 18 may then be rotated byrotating the superconducting element SE (in which case thefluid-agitating element 18 should produce an asymmetric magnetic field,such as by using at least two spaced magnets having alternatingpolarities). Another option is to use a separate drive structure (e.g.,an electromagnetic coil) to form a coupling capable of transmittingtorque to the particular fluid-agitating element (which may be“levitated” by a hydrodynamic bearing; see, e.g., U.S. Pat. No.5,141,327 to Shiobara). While it is of course desirable to eliminate theneed for a dynamic seal or opening in the bag through which a drivestructure (such as a shaft) extends, the particular means used tolevitate and/or rotate the fluid-agitating element 18 is not consideredcritical to practicing the inventions disclosed herein.

The fluid-agitating element 18 is also depicted as including a pluralityof vanes or blades B to improve the degree of fluid agitation. Ifpresent, the vanes or blades B preferably project in a directionopposite the corresponding surface of the rigid portion 14. Theparticular number, type, and form of the vanes or blades B is notconsidered important, as long as the desired degree of fluid agitationfor the particular application is provided. Indeed, in applicationswhere only gentle agitation is required, such as to prevent damage todelicate suspensions or to merely prevent stagnation of the fluid F inthe bag 10, the vanes or blades B need not be provided, as a rotatingsmooth-walled annular element 18 still provides some degree ofagitation.

As explained above, it may be desirable to not only know the generallocation or position of the fluid-agitating element 18 within the bag10, but also to assure its position relative to the motive device 24. Todo so, and in accordance with a second aspect of the invention, therigid portion 14 may be provided with a second receiver 26 to facilitatethe correct positioning of the motive device 24 relative to thefluid-agitating element 18 when held at the home location. In theembodiment shown in FIGS. 1a and 1b , the second receiver 26 takes theform of a second post 28 projecting in a direction opposite the firstpost 20. Preferably, the second post 28 is essentially coaxial with thefirst post 20 (although the post 20 may be a separate component thatfits into a receiver 14 a defined by the second post 28; see FIG. 1c )and is adapted to receive an opening 24 a, such as a bore, in theadjacent end face 24 b forming a part of the housing for the motivedevice 24. Consequently, the second post 28 helps to assure that thealignment between the fluid-agitating element 18 (which is generallyheld in the vicinity of the first receiver 16/post 20, which is the homelocation) and the motive device 24 is proper such that the desiredcoupling for transmitting the levitation or rotational force may beformed.

Preferably, the second receiver 26, such as second post 28, has across-sectional shape corresponding to the shape of the opening 24 a.For example, the second post 28 may be square in cross-section forfitting in a correspondingly-shaped opening 24 a or locator bore.Likewise, the second post 28 could have a triangular cross-sectionalshape, in which case the opening 24 a would be triangular. Myriad othershapes could also be used, as long as the shape of the second receiver26 compliments that of the opening 24 a such that it may be freelyreceived therein. In this regard, it is noted that a system of matchingreceivers and openings may be used to ensure that the fluid-agitatingelement 18 in the bag 10 corresponds to a particular motive device 24.For example, in the case where the fluid-agitating element 18 includes aparticular arrangement of magnets producing a magnetic field thatcorresponds to a particular superconducting element or drive structure,the second receiver 26 may be provided with a certain shape thatcorresponds only to the opening 24 in the motive device 24 having thattype of superconducting element or drive structure. A similar resultcould also be achieved using the relative sizes of the second receiver26 and the opening 24 a, as well as by making the size of the opening 18a such that it only fits on a first receiver 16 having a smaller widthor diameter, and then making the second receiver 26 correspond to anopening 24 a in a motive device 24 corresponding to that element 18.

In many past arrangements where a rigid vessel is used with afluid-agitating element directly supported by a bearing, an externalstructure is provided to which a motive device could be directly orindirectly attached and held in a suspended fashion (see, e.g., U.S.Pat. No. 4,209,259 to Rains et al., the disclosure of which isincorporated herein by reference). This structure serves toautomatically align the motive device with the fluid-agitating elementsupported therein. However, a bag 10 per se is generally incapable ofproviding reliable support for the motive device 24, which can weigh asmuch as twenty kilograms. Thus, the motive device 24 in the embodimentsdisclosed herein for use with a vessel in the form of a bag 10 isgenerally supported from a stable support structure (not shown), such asthe floor, a wheeled, height adjustable platform, or the like. Sincethere is thus no direct attachment with the bag 10, the functionperformed by the second receiver 26 in aligning this device with thefluid-agitating element 18 is an important one.

Another embodiment of the vessel forming one aspect of the presentinvention is shown in FIGS. 3a and 3b . In this embodiment, the vesselis again a bag 10 including a flexible portion 12 and a rigid portion14. The rigid portion 14 is cap or hat-shaped with a peripheral flange22 for attachment to the flexible portion 12 of the bag 10. Theconnection between the two structures may be formed using the varioustechniques described above, and preferably results in afluid-impervious, hermetic seal. The rigid portion 14 includes a firstreceiver 16 in the form of a recess or cavity 30 facing the interior ofthe bag (see action arrow B) for receiving a correspondingly-shapedportion of the fluid-agitating element 18 in the bag 10 and holding itat a home location, at least when oriented as shown in FIG. 3a . Theportion of the fluid-agitating element 18 received in the cavity 30 ispreferably the body 18 b, which as described above is at least partiallymagnetic or ferromagnetic and may optionally support a plurality ofvanes or blades B. Preferably, the body 18 b of the fluid-agitatingelement 18 is circular in cross-section and the cavity 30 is sized andshaped such that the body (which need not include opening 18 a in viewof the absence of post 20) may freely be inserted, rotate, and levitatetherein. However, as with the first embodiment, the fluid-agitatingelement 18 could also be in the form of a conventional magnetic stirrer(which of course would not be levitated), such as a bar having a majordimension less than the corresponding dimension (e.g., the diameter) ofthe cavity 30. In any case, the fluid-agitating element 18 in thisembodiment is again free of direct attachment from the first receiver16, but is held at a home location, even in the event decoupling.

Thus, in the manner similar to that described above with respect to thefirst embodiment, the fluid-agitating element 18 may be positioned inthe first receiver 16 in the bag 10. The bag 10 may then be sealed,folded for storage or shipping, stored or shipped, and ultimatelyunfolded for use. The folding is preferably completed such that thefluid-agitating element 18 is captured in the cavity 30 and remains heldin place during shipping by an adjacent portion of the bag 10.Consequently, upon unfolding the bag 10, the fluid-agitating element 18is at the expected or home location, but remains free of directattachment and ready to be rotated (and possibly levitated). Iflevitated, the levitation height established by the superconductingbearing or hydrodynamic bearing is preferably such that at least aportion of the body 18 b of the fluid-agitating element 18 remainswithin the confines of the cavity 30. This helps to assure that thefluid-agitating element 18 remains held at the home location (that is,in the vicinity of the first receiver 16), even in the case ofaccidental decoupling from the motive device 24. In other words, in theevent of an accidental decoupling, the fluid-agitating element 18 willengage the sidewall of the cavity 30 and simply come to rest therein,which defines the home location. This not only improves the chance of anautomatic recoupling, but also makes the task of manually reforming thecoupling an easy one.

An option to assure that a magnetic fluid-agitating element 18 remainsassociated with the first receiver 16, even if inverted, is to attach anattractive structure, such as a magnet 32 (shown in phantom in FIG. 3a), to the exterior of the rigid portion 14. The non-contact couplingthus established helps ensure that the fluid-agitating element 18remains in the home location prior to being coupled to an externalmotive device. The magnet 32 is removed once the bag 10 is positioned onor in a support structure, such as a container C (see FIG. 2). Such amagnet 32 may also be used with the embodiment of FIG. 1, whicheliminates the need for providing the post 20 with portion 20 a. Themagnet 32 is preferably annular with an opening that is received by thesecond receiver 26, which advantageously helps to ensure the properalignment for forming the coupling.

Yet another option is to provide a frangible adhesive on thefluid-agitating element 18 to hold it in place temporarily in the firstreceiver 16 prior to use. The strength of any adhesive used ispreferably such that the bond is easily broken when the fluid-agitatingelement 18 is levitated in the first receiver 16. Of course, the use ofsuch an adhesive might not be possible in situations where strictregulations govern the purity of the fluid being mixed.

With reference to FIG. 3b , the first receiver 16 in this embodimentalso serves the dual function of helping to align the fluid-agitatingelement 18 relative to an external motive device 24. Specifically, theperiphery of the sidewall 34 and the end wall 36 defining the cavity 30in the rigid portion 14 define a second receiver 26 adapted to receivean opening 24 a formed in an adjacent face of a motive device 24. Asdescribed above, the opening 24 a is preferably sized and shaped forbeing received by the second receiver 26, and may even help to ensurethat the bag 10 is used only with a motive device 24 having the correctsuperconducting element or magnetic structure(s) for levitating and/orrotating the fluid-agitating element 18. For example, in the case wherethe sidewall 34 and end wall 36 provide the second receiver 26 with agenerally cylindrical shape, the opening 24 a is also cylindrical.Preferably, the opening 24 a also has a depth such that the end wall 36rests on the corresponding face 24 c of the motive device 24. Thisfeature may be important to ensure that the gap between thesuperconducting element and/or drive structure in the motive device 24and the at least partially magnetic or ferromagnetic body 18 b of thefluid-agitating element 18 is minimized, which helps to ensure that thestrongest possible coupling is established and that the maximum amountof driving torque is transferred. The gaps are shown as being oversizedin FIG. 3b merely to provide a clear depiction of the relativeinteraction of the structures shown. However, in the case where theentire housing of the motive device 24 is rotated, it may be desirableto provide a certain amount of spacing between the sidewall 34, the endwall 36, and the corresponding surfaces defining the opening 24 a toavoid creating any interference.

FIGS. 4a and 4b show an embodiment similar in some respects to the oneshown in FIGS. 3a and 3b . For example, the rigid portion 14 includes aperipheral flange 22 connected to the flexible portion 12 of the bag 10to form a seal. Also, the rigid portion 14 includes a sidewall 34 andend wall 36 that together define a cavity 30. However, a majordifference is that the cavity 30 of the rigid portion 14 essentiallyfaces outwardly, or toward the exterior of the bag 10 (e.g., in adirection opposite action arrow B). Consequently, the sidewall 34 andend wall 36 define the first receiver 16 for receiving thefluid-agitating element 18, which is shown having an annular body 18 bthat is at least partially magnetic or ferromagnetic and may support aplurality of vanes or blades B. As should be appreciated, the firstreceiver 16 in the form of the periphery of the sidewall 34 provides asimilar receiving function as both the post 20 and the cavity 30 of theother embodiments, since it is capable of maintaining, holding, orconfining the fluid-agitating element 18 substantially in a home orexpected position within the bag 10. The maximum amount of side-to-sidemovement is of course dependent on the size of the opening 18 a in thefluid-agitating element.

Additionally, the outwardly-facing cavity 30 is adapted to serve as thesecond receiver 26 for receiving a portion of a motive device 24 used tolevitate and rotate the fluid-agitating element 18 and serving to alignthe two. Specifically, the motive device 24 may include a head end 24 dadapted for insertion in the cavity 30 to form the desired coupling withthe fluid-agitating element 18 positioned adjacent thereto. As with theembodiments described above, the spacing between the head end 24 d andat least the sidewall 34 is preferably minimized to maximize thestrength of the coupling between the motive device 24 and thefluid-agitating element 18. Moreover, in view of the rigid nature of therigid portion 14, the end face 24 b of the head end 24 d may restagainst and assist in supporting the bag 10 (which, as described above,may be positioned in a separate, semi-rigid container (not shown)).

In each of the above-referenced embodiments, the possible use of alevitating fluid-agitating element 18 with a superconducting bearing ora hydrodynamic bearing is described. In such systems, a real possibilityexists that the fluid-agitating element 18 might accidentally decoupleor disconnect from the motive device 24, such as if the fluid is viscousor the amount of torque transmitted exceeds the strength of thecoupling. In a conventional bag, the process of reestablishing thecoupling is extraordinarily difficult, since the location of thefluid-agitating element 18 within the bag 10 is unknown. In a sterileenvironment, opening the bag 10 and using an implement to reposition or“fish” out the fluid-agitating element 18 is simply not an option. Thus,an added advantage of the use of the first receiver 16 in each of theabove-referenced embodiments is that, despite being free from directattachment, it still serves the function of holding the fluid-agitatingelement 18 at the home location in instances where accidental decouplingoccurs. This significantly reduces the downtime associated with such anevent, since the general position of the fluid-agitating element 18 isknown. The use of a first receiver in the bag 10 also improves thechances of automatic recoupling, since the fluid-agitating element 18remains generally centered relative to the motive device 24 and heldgenerally at the home location, even when decoupling occurs.

A related advantage is provided by forming the first receiver 16 in oron a rigid portion 14 of the bag 10. Specifically, in the case where afluid-agitating element rests on a surface of a bag, the contact overtime could result in damage and could even lead to an accidentalperforation, which is deleterious for obvious reasons. The possibilityfor such damage or perforation also exists when a levitatingfluid-agitating element 18 accidentally decouples. Advantageously, thepotential for such damage or perforation is substantially eliminated inthe foregoing embodiments, since the first receiver 16 helps to keep thefluid-agitating element 18 adjacent to the flange 22 of the rigidportion 14, which is generally thicker and less susceptible to beingdamaged or perforated. In other words, if the fluid-agitating element 18becomes decoupled, it only engages or contacts the rigid portion 14 ofthe bag 10. Thus, it is preferable for the flange 22 to be oversizedrelative to the fluid-agitating element 18. While the embodiments ofFIGS. 1-4 are described as bags 10 including both a flexible portion 12and a rigid portion 14, it should be appreciated that the presentinvention extends to a completely rigid vessel (that is, one made ofmetal, glass, rigid plastics, or the like). In the case of a rigidvessel, the post 20 preferably includes a portion 20 a for capturing thefluid-agitating element 18 thereon, but without any other means ofdirect attachment or bearing.

Up to this point, the focus has been on a fluid-agitating element 18capable of levitating in the vessel. However, as briefly noted above,the inventions described herein may also be applied to a bag 10 incombination with a fluid-agitating element 18 directly supported by oneor more bearings. For example, as shown in FIGS. 5a and 5b , the firstreceiver 16 associated with the rigid portion 14 of the bag 10 may be inthe form of an inwardly-projecting post 20 including a slide bearing 40for providing direct support for the fluid-agitating element 18. Thebearing 40 is preferably sized and shaped such that it fits into anopening 18 a forming in the fluid-agitating element 18, which may reston the adjacent surface of the post 20 or may be elevated slightly aboveit. In either case, it should be appreciated that the first receiver 16receives and holds the fluid-agitating element 18 in a home location,both during shipping and later use.

In view of the direct nature of the support, the material forming theslide bearing 40 is preferably highly wear-resistant with goodtribological characteristics. The use of a slide bearing 40 is preferredin applications where the bag 10 is disposable and is merely discarded,since it is less expensive than a corresponding type of mechanicalroller bearing (and is actually preferred even in the case where the bag10 is reused, since it is easier to clean). However, it is within thebroadest aspects of the invention to provide the first receiver 16 witha conventional roller bearing for providing direct, low-friction,rolling support for the rotating fluid-agitating element 18, althoughthis increases the manufacturing expense and may not be acceptable incertain applications.

The rigid portion 14 of the bag 10 in this embodiment may furtherinclude a second receiver 26 in the form of a second post 28 coextensiveand coaxial with the first post 20. The second post 28 is received in anopening 24 a formed in an end face 24 b of a motive device 24. In viewof the direct support provided for the fluid-agitating element 18 by thebearing 40, the motive device 24 in this case includes only a drivestructure DS (shown in phantom in FIG. 5b ) for forming a coupling withthe body 18 b, which is magnetic or ferromagnetic (iron, magnetic steel,etc.). The drive structure DS may be a permanent magnet or may beferromagnetic, as necessary for forming the coupling with thefluid-agitating element 18, which may be disc-shaped, cross-shaped, anelongated bar, or have any other suitable shape. The drive structure DSmay be rotated by a direct connection with a motor (not shown), such asa variable speed electric motor, to induce rotation in thefluid-agitating element 18. Alternatively, the drive structure DS may bean electromagnet with windings to which current is supplied to cause themagnetic fluid-agitating element 18 rotate and possibly levitateslightly to create a hydrodynamic bearing (see, e.g., U.S. Pat. No.5,141,327, the disclosure of which is incorporated herein by reference).Again, it is reiterated that the particular type of motive device 24employed is not considered critical to the present invention.

FIGS. 6a and 6b show an embodiment of the bag 10 in which the firstreceiver 16 is in the form of a cavity 30 formed in the rigid portion 14and facing inwardly. A bearing 40 is provided in the cavity 30 forproviding direct support for a fluid-agitating element 18 positionedtherein. As with the embodiment described immediately above, the bearing40 may be a slide bearing adapted for insertion in the opening 18 a ofthe fluid-agitating element 18 formed on the head end of a post 42. Thepost 42 may be supported by or unitarily formed with the end wall 36.Despite the depiction of a slide bearing 40, it is reiterated that theparticular type of bearing used is not considered critical, as long asrotational support is provided for the fluid-agitating element 18 andthe other needs of the particular fluid-agitating operation are met(e.g., low friction, reduced expense, easy clean-up).

The body 18 b of the fluid-agitating element 18, which is at leastpartially magnetic or ferromagnetic, is sized to fit within the sidewall34 defining the cavity 30 and, thus, is capable of rotating therein asthe result of an externally-applied, non-contact motive force. Theperiphery of the sidewall 34 also defines a second receiver 26 forreceiving a corresponding opening 24 a in a motive device 24, which inview of the direct support provided by bearing 40 need only provide theforce necessary to rotate the fluid-agitating element 18 in anon-contact fashion.

As should be appreciated, the embodiment shown in FIGS. 7a and 7b is thedirect support counterpart for the embodiment shown in FIGS. 4a and 4b .The rigid portion 14 again includes a cavity 30 facing outwardly ortoward the exterior of the bag 10 and a first receiver 16 for receivingand defining a home location for a fluid-agitating element 18. The firstreceiver 16 includes a bearing 40 for supporting the fluid-agitatingelement 18, which again is at least partially magnetic or ferromagnetic.The bearing 40 may be a slide bearing formed on the head end of a post44 integral with the end wall 36 of the rigid portion 14 and adapted forfitting into an opening or recess 18 a in the fluid-agitating element18, or may be a different type of bearing for providing supporttherefor.

The motive device 24 includes a head end 24 d adapted for insertion in asecond receiver 26 defined by the cavity 30. This head end 24 dpreferably includes the drive structure DS that provides the force forcausing the at least partially magnetic or ferromagnetic fluid-agitatingelement 18 to rotate about bearing 40. In FIGS. 7a and 7b , it is notedthat the fluid-agitating element 18 includes an optional dependingportion 18 d that extends over the sidewall 34. As should beappreciated, this portion may also be magnetized or ferromagnetic suchthat a coupling is formed with the drive structure DS. A similar type offluid-agitating element 18 could also be used in the levitation schemeof FIGS. 4a and 4 b.

Turning now to FIG. 8, and as noted in the foregoing description, it mayalso be desirable to provide the bag 10 with an integral sparger 100including means for forming bubbles in the fluid. In the illustratedembodiment, the sparger 100 includes a face portion 102 a for attachingto the bag 10 and a tubular projecting portion 102 b for coupling withan external source of gas, such as through a tube U. The face portion102 a may comprise a disk-shaped piece of rigid plastic material, andmay be welded (such as by a circular weld 103) directly to the flexiblematerial forming the bag 10 adjacent the fluid F when present such thata fluid-impervious seal results.

Gas introduced through the tube U from a remote source (not shown) thusenters the bag 10, passing through any fluid present. In the illustratedembodiment, the means for forming bubbles in the gas entering the fluidcomprises a perforated piece of plastic film 104 may also be securedadjacent the face portion 102 a of the sparger 100, such as by welding(e.g., a circular weld 105). To create the small bubbles desired formany bioprocessing applications, the holes in the film 104 arepreferably in the sub-millimeter range. Alternatively, a porous film maybe used, various types of which are generally well known in the art(see, e.g., U.S. Pat. No. 4,814,124, incorporated herein by reference).In either case, the bag 10 with the integral sparger 100 may simply bedisposed upon recovering all or part of the fluid, or alternatively aproduct therefrom.

Instead of providing a separate sparger 100, it is also possible tocombine it with the rigid portion 14 of the bag 10 for receiving thefluid-agitating element 18 and providing the desired centering/alignmentfunction. Thus, as shown in FIG. 9, the rigid portion 14 is welded tothe bag 10, as described above, preferably along the bottom and suchthat a fluid-impervious seal is formed. A receiver in the form of a post20 may be removably attached to the rigid portion 14 through the opening(not shown) in the fluid-agitating element 18 (such as by providing athreaded bore in the rigid portion for receiving a threaded end of thepost, or as shown in FIG. 1c , a bore 14 a having a groove forestablishing a snap-fit engagement with the post), and may include anoversized head for providing a retaining function. As described above, asecond receiver 26 in the form of a recess or cavity in the rigidportion 14 may also be provided for receiving an external motive device,such as a rotating drive magnet or superconducting element (not shown).

The face 14 c of the rigid portion 14 further includes a first passage14 d in communication with both the interior of the bag 10 and a secondpassage 14 e leading to an external source of gas via a tube U. Gasintroduced through the tube U thus exits into the interior of the bag 10through the first passage 14 d, which may be associated with aperforated piece of material 106 comprising the means for forming thebubbles. In the preferred embodiment, the first passage 14 d is annularand includes seating ledges 14 f for receiving the material 106, whichtakes the form of an annular piece of plastic film having a plurality ofholes or apertures to form the perforations (which, again, arepreferably sized in the sub-millimeter range) that is welded in place.Advantageously, the sparger 100 thus created in the illustratedembodiment releases the bubbles in close proximity to thefluid-agitating element 18, thus enhancing their dispersion throughoutthe fluid.

In yet another, but similar embodiment shown in FIGS. 10a and 10b , thesparger 100 is integral with the rigid portion 14 connected to the bag10, which may again include a receiver in the form of an inwardlyprojecting post 20 for receiving the fluid-agitating element 18 and anoutwardly directed alignment structure 26. The post 20 in thisembodiment includes an inlet 21 a for connecting with a tube U coupledto an external source of gas (not shown), such as through an opening oropen end of the bag, and an outer wall 21 b formed of a perforated orgas permeable material that serves as the means for forming bubbles inthis embodiment. To add rigidity to the post 20, a center support 21 cmay also be provided concentric with the outer wall 20 b.

Thus, gas passing through the tube U exits the outer wall 20 b of thepost 20 as bubbles (the size of which depend on the size of theperforations made, which again are preferably in the sub-millimeterrange). As shown in FIG. 10b , when the fluid-agitating element 18 islevitated and/or rotated by an adjacent, but external motive device 24,the bubbles are released adjacent the opening 18 a and dispersedthroughout the fluid F. Once use of the bag 10 is complete, it may thensimply be discarded along with the sparger 100.

Besides a sparger 100 and/or a magnetic fluid-agitating element 18, itmay also be desirable to provide disposable means in the bag 10 tofacilitate sensing characteristics of the fluid, such as the pH, oxygencontent, temperature, etc. Thus, in the embodiment of FIG. 11, the bagincludes a rigid receiver 200 for receiving a sensor S, such receivercomprised of a translucent or transparent (preferably glass),close-ended tube G and a fiber optic cable L for transmitting light toand receiving back the reflected light (note bidirectional arrows). Thereceiver 200 includes a face 202 a having a periphery to which the bag10 is attached, such as by welding, to form a fluid impervious seal. Atubular portion 202 b of the receiver 200 receives a bushing 204, whichin turn receives the closed end of the transparent tube G and allows itto pass into contact with the fluid F when present in the bag 10. Asealing tube 206, preferably made of flexible plastic or an elasticmaterial, couples the bushing 204 to the tubular portion 202 b of thereceiver 200 (which may include a slightly oversized, frusto-conicalportion defining a hold-assist ledge for the tube). Fasteners, such ascable ties 208, may help to removably secure the sealing tube 206 inplace, although other means for sealing could be used instead, such asadhesives or the like. The important point is that no appreciable amountof fluid can pass the tube G once inserted in the receiver 200.

The tube G may carry a sensor S in the form of a fluorescent sensingelement E, preferably by way of external attachment to the closed,transparent or translucent end (which thus forms a window for allowinglight to be transmitted to the sensing element). As is known in the art,this element E may change its fluorescence characteristics in responseto change in the pH, dissolved oxygen, carbon dioxide, or temperature ofthe fluid it is touching. The fluorescence characteristics can then bemeasured by external apparatus capable of illuminating the sensitiveelement E, such as through the cable L, and the transparent closed endof the tube G. As should be appreciated, this type of sensitive elementE is not only disposable, but also advantageously does not require anypower or leads. As a result of this arrangement, the above mentionedparameters of the fluid can be measured non-invasively, and the tube Gsimply discarded along with the bag 10 when the bioprocessing operationis complete. The receiver 200 may thus be considered to form an opticalport with a sensitive element E attached to an inner surface of anoptical window. An example of an off-the-shelf sensor element E is onemanufactured by PreSens (or Precision Sensing) GmbH Josef-Entert-Str. 9D-93053 Regensburg Germany.

Obvious modifications or variations are possible in light of the aboveteachings. For example, instead of forming the rigid portion 14 as partof the bag 10 by forming a seal at an interface between the two, itcould also be positioned in contact to an inner or outer surface of thebag and attached using vacuum-forming techniques, adhesives, or thelike. For example, in the cap-shaped embodiment of FIG. 3a , the bag 10would essentially line the inside surfaces of the sidewall 34 and endwall 36. Likewise, in the embodiment of FIG. 4a , the bag 10 would coverthe sidewall 34 and end wall 36. In both cases, the need for the flange22 may be eliminated. It is also possible to provide any of the firstreceivers with a tapered or frusto-conical engagement surface that mateswith a corresponding surface on the fluid-agitating element, asdisclosed in my co-pending patent application Ser. No. PCT/US01/31459,the disclosure of which is incorporated herein by reference. Theintegral sparger 14 may also be provided in the embodiment in which therigid portion 14 is cap or cup-shaped, such as by providing theperforated/permeable material (whether film, rigid, or otherwise) forforming the bubbles along the peripheral flange 22, sidewall 34, or endwall 36, and providing a passage to allow for gas to communicate with itfrom a remote source (such as through an external tube).

The foregoing descriptions of various embodiments of the presentinventions have been presented for purposes of illustration anddescription. These descriptions are not intended to be exhaustive or tolimit the invention to the precise forms disclosed. The embodimentsdescribed provide the best illustration of the principles of theinvention and its practical applications to thereby enable one ofordinary skill in the art to utilize the invention in variousembodiments and with various modifications as are suited to theparticular use contemplated. All such modifications and variations arewithin the scope of the invention as determined by the appended claimswhen interpreted in accordance with the breadth to which they arefairly, legally and equitably entitled.

The invention claimed is:
 1. A container system comprising: a bagcomprised of a sheet of a flexible polymeric material, the bag having aninterior surface and a chamber, the chamber being adapted to hold afluid; a sparger secured to the bag so that a compartment is formed inthe chamber within the interior surface of the bag, at least a portionof the sparger being comprised of a sparging sheet comprised of aflexible sheet of a gas permeable material; and a rigid disk including atube, the rigid disk coupled with the bag so that a passage bounded bythe tube communicates with the compartment; wherein the flexible sheetof the gas permeable material is connected to the rigid disk so as toform the compartment; wherein the rigid disk is connected to the bag bya weld.
 2. The container system of claim 1, wherein the flexible sheetof the gas permeable material is connected to the rigid disk by a weld.3. The container system of claim 2, wherein the weld connecting theflexible sheet of the gas permeable material to the rigid disk iscircular.
 4. The container system of claim 1, wherein the weldconnecting the rigid disk to the bag is circular.
 5. A container systemcomprising: a bag comprised of a sheet of a flexible polymeric material,the bag having an interior surface and a chamber, the chamber beingadapted to hold a fluid; a sparger secured along an interior of the bagand forming a compartment, at least a portion of the sparger beingcomprised of a sparging sheet comprised of a flexible sheet of a gaspermeable material; and a rigid disk connected to the bag, the rigiddisk including a tube coupled with the bag so that a passage bounded bythe tube communicates with the compartment; wherein the flexible sheetof the gas permeable material is connected to the rigid disk so as toform the compartment.
 6. The container system of claim 5, wherein theflexible sheet of the gas permeable material is connected to the rigiddisk by a weld.
 7. The container system of claim 6, wherein the weld iscircular.
 8. The container system of claim 5, wherein the rigid disk isconnected to the bag by a weld.
 9. The container system of claim 8,wherein the weld is circular.
 10. A container system comprising: a bagcomprised of a sheet of a flexible polymeric material, the bag having aninterior surface and a chamber, the chamber being adapted to hold afluid; a sparger forming a compartment in the chamber of the bag, atleast a portion of the sparger being comprised of a sparging sheetcomprised of a flexible sheet of a gas permeable material; a rigid diskconnected to the sparging sheet the rigid disk including a tube and therigid disk being coupled with the sparging sheet and the bag so that apassage bounded by the tube communicates with the compartment; whereinthe rigid disk is connected to the bag by a weld.
 11. The containersystem of claim 10, wherein the flexible sheet of gas permeable materialis connected to the rigid disk so as to form the compartment.
 12. Thecontainer system of claim 10, wherein the flexible sheet of gaspermeable material is connected to the rigid disk by a weld.
 13. Thecontainer system of claim 12, wherein the weld connecting the flexiblesheet of gas permeable material to the rigid disk is circular.
 14. Thecontainer system of claim 10, wherein the weld is circular.
 15. Acontainer system comprising: a bag comprised of a sheet of a flexiblepolymeric material, the bag having an interior surface and a firstcompartment adapted to hold a fluid; a sparger forming a secondcompartment in the first compartment of the bag, at least a portion ofthe sparger being comprised of a sparging sheet comprised of a flexiblesheet of a gas permeable material; and a rigid disk connected to thebag, the rigid disk including a tube and being coupled with the spargingsheet and the bag so that a passage bounded by the tube communicateswith the second compartment and the gas permeable material of theflexible sheet of the sparger communicates with the first compartment ofthe bag; wherein the flexible sheet of the gas permeable material isconnected to the rigid disk so as to form the second compartment. 16.The container system of claim 15, wherein the flexible sheet of the gaspermeable material is connected to the rigid disk by a weld.
 17. Thecontainer system of claim 16, wherein the weld is circular.
 18. Thecontainer system of claim 15, wherein the rigid disk is connected to thebag by a weld.
 19. The container system of claim 18, wherein the weld iscircular.
 20. A container system comprising: a bag comprised of a sheetof a flexible polymeric material, the bag having an interior surface anda chamber, the chamber being adapted to hold a fluid; a sparger securedalong an interior of the bag and forming a compartment, at least aportion of the sparger being comprised of a sparging sheet comprised ofa flexible sheet of a gas permeable material; and a rigid disk connectedto the bag, the rigid disk including a tube, the rigid disk beingcoupled with the bag so that a passage bounded by the tube communicateswith the compartment; wherein the flexible sheet of the gas permeablematerial is connected to the rigid disk by a weld.